- Itanapraced blocks LRRK2 expression and LRRK2-mediated neurotoxicity
- Itanapraced ready to advance to Phase 2 in Parkinson’s disease patients with and without genetic mutation
NEW YORK and SINGAPORE, Dec 11 (Bernama-GLOBE NEWSWIRE) --CERESPIR INCORPORATED a pharmaceutical company engaged in the discovery and development of disease-modifying therapeutics for the treatment of neurodegenerative diseases, and THE NATIONAL NEUROSCIENCE INSTITUTE SINGAPORE, a national and international center of excellence in neuroscience with its mission to improve lives through integrated clinical service, research and education, announced today that they have obtained animal proof of concept for CERESPIR’s clinical stage compound itanapraced in Parkinson’s disease models. Specifically, itanapraced, which was previously tested with positive results in patients with mild cognitive impairment (MCI), was shown to block the expression of LRRK2 and, additionally, prevent neurotoxicity resulting in the preservation of healthy dopaminergic neurons. These data support the initiation of Phase 2 trials in Parkinson’s disease and may have broad applicability for neurodegenerative diseases. The study was conducted in collaboration with Professor Tan Eng King, Deputy Medical Director, Senior Consultant Neurology and Research Director at the National Neuroscience Institute, Singapore, Co-Director of the US National Parkinson Foundation International Center of Excellence, and Dr. Li Zeng, a senior research scientist at the National Neuroscience Institute, Singapore.
Itanapraced works via a novel target that is central to the neurodegenerative process causing dysregulation of the cellular response to oxidative stress. Specifically, itanapraced is the first of a new class of molecules known as AICD inhibitors that bind to AICD (amyloid precursor protein intracellular domain) and inhibits its transcriptional activity. Under conditions of acute or chronic oxidative stress, AICD interacts with FoxO3a (a critical component of the stress response system), to promote the expression of pro-apoptotic factor BIM, causing neuronal death. Parkinson’s disease is a common, progressive neurodegenerative disorder associated with loss of midbrain dopaminergic neurons which produce the essential neurotransmitter, dopamine. LRRK2 gain of function mutants are responsible for the majority of cases of familial Parkinson’s disease. Additionally, LRRK2 kinase activity is aberrantly increased in vulnerable dopamine neurons by oxidative mechanisms involving α-synuclein and mitochondrial impairment, suggesting LRRK2 inhibition will be useful for the majority of Parkinson’s disease patients. Previously the research team led by Professor Tan and Dr Zeng showed that AICD becomes transcriptionally active when it is phosphorylated by LRRK2, leading to loss of dopaminergic neurons in vivo (Chen et al., Sci. Signal. 10, eaam6790 (2017). The investigators now aim to publish, in a peer-reviewed scientific journal, the new data showing the ability of itanapraced to block expression and neurotoxicity of LRRK2.
Itanapraced works via a novel target that is central to the neurodegenerative process causing dysregulation of the cellular response to oxidative stress. Specifically, itanapraced is the first of a new class of molecules known as AICD inhibitors that bind to AICD (amyloid precursor protein intracellular domain) and inhibits its transcriptional activity. Under conditions of acute or chronic oxidative stress, AICD interacts with FoxO3a (a critical component of the stress response system), to promote the expression of pro-apoptotic factor BIM, causing neuronal death. Parkinson’s disease is a common, progressive neurodegenerative disorder associated with loss of midbrain dopaminergic neurons which produce the essential neurotransmitter, dopamine. LRRK2 gain of function mutants are responsible for the majority of cases of familial Parkinson’s disease. Additionally, LRRK2 kinase activity is aberrantly increased in vulnerable dopamine neurons by oxidative mechanisms involving α-synuclein and mitochondrial impairment, suggesting LRRK2 inhibition will be useful for the majority of Parkinson’s disease patients. Previously the research team led by Professor Tan and Dr Zeng showed that AICD becomes transcriptionally active when it is phosphorylated by LRRK2, leading to loss of dopaminergic neurons in vivo (Chen et al., Sci. Signal. 10, eaam6790 (2017). The investigators now aim to publish, in a peer-reviewed scientific journal, the new data showing the ability of itanapraced to block expression and neurotoxicity of LRRK2.
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